The proposed research deals with two aspects of obstructive sleep apnea (OSA): pathogenesis and treatment. We review the general theory that OSA consists of periodic occlusion of the oropharynx resulting from an imbalance between dilitory forces (contraction of oropharyngeal muscles) and constrictive forces (transpharyngeal pressure during inspiration), and we advance a rationale for treating OSA with blockers of post-synaptic inhibition, of pre-synaptic inhibition, and of opiate action. Results of preliminary studies in patients with OSA reveal elevated nasopharyngeal resistance while awake and hypotonia of palatal muscles at sleep onset. These findings support our theory of pathogenesis of OSA. Other recently obtained results reveal amelioration of OSA by treatment with strychnine, a blocker of post-synaptic inhibition. We have performed alternate night crossover studies on 4 patients with OSA. Strychnine produces a 7-fold decrease in the prevalence of periodic apnea and improves oxygenation. Our results indicate that this amelioration of OSA results from activation of oropharyngeal muscles, particuarly the tensor palatini and the genioglossus. To investigate the pathogenesis of oropharyngeal occlusion in OSA, we propose to examine the flow-resistive properties of the oropharynx in patients with OSA while awake. An elevated value will indicate structural encroachment on the oropharyngeal lumen. We will assess the contribution of fat deposition and changes in upper airway muscle activity to oropharyngeal resistance. We will correlate oropharyngeal muscle activity with resistance at sleep onset and during sleep, and thereby, test the proposition that sleep increases nasopharyngeal resistance by causing hypotonia of oropharyngeal muscles. An animal model will be utilized to probe the effects of sleep disruption secondary to repeated airway occlusion in rabbits. To evaluate a new avenue for therapy of OSA, we will investigate the action of a blocker of post-synaptic inhibition on OSA and on oropharyngeal muscle activity. The possible use of blockers of pre-synaptic inhibition or of endogenous opiates will be explored in the animal model of OSA. If the results of these experiments are promising, these agents will be used in clinical trials in patients with OSA.